Dataset Information

Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance.

ABSTRACT: Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics and a BCR-ABL model of CML, we observed cross talk between Wnt/β-catenin signaling and the interferon-regulatory factor 8 (Irf8). In normal hematopoiesis, activation of β-catenin results in up-regulation of Irf8, which in turn limits oncogenic β-catenin functions. Self-renewal and myeloproliferation become dependent on β-catenin in Irf8-deficient animals that develop a CML-like disease. Combined Irf8 deletion and constitutive β-catenin activation result in progression of CML into fatal blast crisis, elevated leukemic potential of BCR-ABL-induced LICs, and Imatinib resistance. Interestingly, activated β-catenin enhances a preexisting Irf8-deficient gene signature, identifying β-catenin as an amplifier of progression-specific gene regulation in the shift of CML to blast crisis. Collectively, our data uncover Irf8 as a roadblock for β-catenin-driven leukemia and imply both factors as targets in combinatorial therapy.

SUBMITTER: Scheller M

PROVIDER: S-EPMC3804946 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance.

Scheller Marina M Schönheit Jörg J Zimmermann Karin K Leser Ulf U Rosenbauer Frank F Leutz Achim A

The Journal of experimental medicine 20131007 11

Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics and a BCR-ABL model of CML, we observed cross talk between Wnt/β-catenin signaling and the interferon-regulatory factor 8 (Irf8). In normal hematopoiesis, activation of β-catenin results in up-regulation of Irf8, which in turn limits oncogenic β-catenin functions. Self-renewal and myeloproliferation become dependent on β-catenin in Irf8-deficien ...[more]

PMID: 24101380

Similar Datasets

Project description:BackgroundOvarian cancer is the most lethal gynecologic malignancy worldwide. Olaparib, an inhibitor of poly (ADP-ribose) polymerase (PARP), is becoming widely used in ovarian cancer treatment. The overall survival of ovarian cancer has not been significantly changed over the past decades and ovarian cancer has become increasingly resistant to the Olaparib. Ubiquitin-conjugating enzyme E2S (UBE2S) has been proved to promote malignant behaviors in many cancers. However, the function of UBE2S in the development and Olaparib resistance of ovarian cancer are unclear.Materials and methodsIn this study, we detected the expression of UBE2S in normal fallopian tube (FT) and HGSOC tissues. A2780 and SKOV3 cells were stably transfected with PCMV-UBE2S, PCMV-UBE2S-C95S, UBE2S shRNAs, and negative controls. The CCK8 assay and clonogenic assay were conducted to analyze ovarian cancer proliferation and Olaparib resistance. The transwell assay was performed to determine the migration and invasion of ovarian cancer cells. The relative protein levels of the Wnt/β-catenin signaling pathway were tested using western blot. The ovarian cancer cells were treated with XAV-939 to investigate the role of Wnt/β-catenin signaling pathway in Olaparib resistance. Moreover, we repeated some above procedures in the xenograft model.ResultsThe results demonstrated that UBE2S was highly upregulated in HGSOC and that high UBE2S expression was correlated with poor outcomes in HGSOC. UBE2S promoted ovarian cancer proliferation and drived the migration and invasion of ovarian cancer cells. UBE2S activated the Wnt/β-catenin signaling pathway in ovarian cancer resulting in Olaparib resistance in vitro and in vivo. Furthermore, UBE2S enhanced the proliferation and Olaparib resistance of ovarian cancer in its enzymatic activity dependent manner.ConclusionsThese data suggest a possible molecular mechanism of proliferation and metastasis of ovarian cancer and highlight the potential role of UBE2S as a therapeutic target in ovarian cancer.

Dataset Information

Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance.

Publications

Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets